The Paks (p21-activated kinases) Pak1, Pak2 and Pak3 are among the most studied effectors of the Rho-family GTPases, Rac, Cdc42 (cell division cycle 42) and Chp (Cdc42 homologous protein). Pak kinases influence a variety of cellular functions, but the process of Pak down-regulation, following activation, is poorly understood. In the present study, we describe for the first time a negative-inhibitory loop generated by the small Rho-GTPases Cdc42 and Chp, resulting in Pak1 inhibition. Upon overexpression of Chp, we unexpectedly observed a T-cell migration phenotype consistent with Paks inhibition. In line with this observation, overexpression of either Chp or Cdc42 caused a marked reduction in the level of Pak1 protein in a number of different cell lines. Chp-induced degradation was accompanied by ubiquitination of Pak1, and was dependent on the proteasome. The susceptibility of Pak1 to Chp-induced degradation depended on its p21-binding domain, kinase activity and a number of Pak1 autophosphorylation sites, whereas the PIX- (Pak-interacting exchange factor) and Nck-binding sites were not required. Together, these results implicate Chp-induced kinase autophosphorylation in the degradation of Pak1. The N-terminal domain of Chp was found to be required for Chp-induced degradation, although not for Pak1 activation, suggesting that Chp provides a second function, distinct from kinase activation, to trigger Pak degradation. Collectively, our results demonstrate a novel mechanism of signal termination mediated by the Rho-family GTPases Chp and Cdc42, which results in ubiquitin-mediated degradation of one of their direct effectors, Pak1.
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Research Article|
May 29 2007
Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp
Monika Weisz Hubsman;
Monika Weisz Hubsman
*Department of Molecular Genetics, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, 1 Efron St. Bat-Galim, Haifa 31096, Israel
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Natalia Volinsky;
Natalia Volinsky
†Department of Pharmacology, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, 1 Efron St. Bat-Galim, Haifa 31096, Israel
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Edward Manser;
Edward Manser
‡Institute for Medical Biology, Proteos Building, 61 Biopolis Drive, Singapore
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Deborah Yablonski;
Deborah Yablonski
1
†Department of Pharmacology, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, 1 Efron St. Bat-Galim, Haifa 31096, Israel
1Correspondence may be addressed to either of these authors (email debya@tx.technion.ac.il or aronheim@tx.technion.ac.il).
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Ami Aronheim
Ami Aronheim
1
*Department of Molecular Genetics, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, 1 Efron St. Bat-Galim, Haifa 31096, Israel
1Correspondence may be addressed to either of these authors (email debya@tx.technion.ac.il or aronheim@tx.technion.ac.il).
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Publisher: Portland Press Ltd
Received:
November 13 2006
Revision Received:
March 05 2007
Accepted:
March 13 2007
Accepted Manuscript online:
March 13 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2007 Biochemical Society
2007
Biochem J (2007) 404 (3): 487–497.
Article history
Received:
November 13 2006
Revision Received:
March 05 2007
Accepted:
March 13 2007
Accepted Manuscript online:
March 13 2007
Citation
Monika Weisz Hubsman, Natalia Volinsky, Edward Manser, Deborah Yablonski, Ami Aronheim; Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp. Biochem J 15 June 2007; 404 (3): 487–497. doi: https://doi.org/10.1042/BJ20061696
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